CA2049274A1 - Flurbiprofen intermediates & processes - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

There are provided 2-(3-fluoro-4-nitrophenyl)-cyano-propionic acid lower alkyl esters, useful as inter-mediates in the preparation of flurbiprofen, as well as processes for their preparation and processes for their conversion to flurbiprofen.

Description

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This invention relates to flurbiprofen and methods for its preparation. More particularly, it relates to novel intermediates useful in the synthesis o~ flurbi-profen, processes for preparing such novel intermediates and use of the intermediates in preparation of flurbi-profen.

Flurbiprofen, which is chemically 2-(2-fluoro-4-biphenylyl) propionic acid o~ the formula:
~,j ~lo O ~ 3 F

is a well-known and well accepted pharmaceutical, commonly prescribed as an anti-in~lammatory, analgesic and anti-pyretic. It is described in Canadian patent 831 J 029 Adams et al., issued December 30, 1969. It continues to be of major importance as a human medicine, and so there is a continuing incentive to devise improved commercial methods for its synthesis and production.

Aforementioned Canadian patent 831,029 describes the preparation o~ flurbiprofen and its analogs from biphenyl and its derivatives. One such process is the reaction of an ester o~ a 4-biphenylyl acetic acid with diethyl carbonate and sodium ethoxide followed by hydroly-sis o~ the malonic ester which is formed and decarboxyla-tion of the resulting malonic compound by heating. Another process disclosed therein is the reduction of the corre-sponding ~-hydroxy acid.

U.S. patents 4,266,069 and 4,398,035 Walker, which are essentially identical to one another as regards their technical teachings, describe higher yield processes 2~27'~

for making flurbiprofen, utili~ing as inte~mediates malonic acid or dialkyl malonate compounds of the formula /c ~o~
~,C - C ~ c og R~

1`1 ~1 where R is hydrogen or lower alkylO These compounds can be coupled to benzene by means of the Gomberg-Bachmann reaction to form biphenylyl compounds, followed by decar-boxylation to the desired biphenylyl-propionic acid com-pounds. Unexpectedly high yields of biphenylyl compounds from the coupling reaction are claimed in these patents.
Howaver, the specific compound used in flurbiprofen prep-aration according to thi~ process, methyl-(4-amino~3-flurophenyl)-2-cyano propionate, i5 an air-unstable oil which quickly darkens. In the process described therein, the p-aminophenyl malonate compounds are prepared by reduction of the corresponding p-nitrophenyl malonate compounds, which in turn are prepared by reaction of dialkyl malonates with l-chloro-3-fluoro-4-nitrobenzene in the presence of a base.

It is an object of the present invention to provide novel processes for preparing flurbiprofen, and novel intermediates for use in such processes.

It is a ~urther object of the present invention to provide processes for making such novel intermediates.

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2 0 ll 9 2 1 ll According to a first aspect, the present inven-tion provides, as novel compounds useful as intermediates in flurbiprofen synthesis, 2-(3-fluoro-~-nitrophenyl~ 2-cyano propionic acid lower alkyl esters, and their 4-amino analogs.

According to another aspect, there is provided a process of preparing 2-(2-fluoro-3-nitrophenyl)-2-cyano propionic acid lower alkyl esters, which comprises reacting 2,4-difluoro nitrobenzene with a lower alkyl-~2-cyano) propionate.

According to a further aspect, there are provided processes of converting the novel intermediates defined above to flurbiprofen.

The term 'llower alkyl" as used herein, in connec-tion with the propionic esters, means Cl C4 alkyl groups.
Most preferred among these is methyl, and so the invention will be described below with reference to the methyl esters thereof.

The accompanying single Figure of drawings is a diagrammatic process flow sheet illustrating the chemical compounds of the present invention and the preferred processes for their preparation and use.

With reference to the Figure, the starting material for the preferred process of the present inven-tion, compound (I) is 2-4-difluoro nitrobenzene, a commer-cially available compound. This is chemically converted to methyl-[2-(3--fluoro-4-nitro)-2 cyano]propionate, compound (II), by one of two processes. It may be converted direct-ly, by reaction with methyl-2-cyano propionate~ in solution in an aprotic solvent such as dimethylEormamide under alkaline conditions. Alternatively, compound (I) is first 7 ~

reacted with methyl cyano acetate under similar conditions, to effect nucleophilic substitukion of the 4-fluoro group of compound (I) with the cyano acetate group through position 2 thereof. This product is then extractad and subsequently reacted wi~h a methylating agent such as dimethyl sulphate to form methyl ~-(3-fluoro-4-nitro-phenyl)-2-cyano propionate, compound (II).

This compound (II) is a novel compound, and constitutes a principle feature of the present invention.
Nucleophilic substitution of the appropriate fluorine group with compounds carrying a cyano group and an ester group attached to the same carbon atom proceed just as readily as nucleophilic substitution of compounds bearing two ester groups as used in the aforementioned process shown in the Walker patents. Certain unexpected advantages flow from the use of these cyano intermediates of the present inven-tion, as one proceeds to the synthesis of flurbiprofen from them.
For example, in the preferred process of the present invention, compound (II) is next converted to compound (III), its amino analog, by hydrogenation, e.g.
with hydrogen over a platinum catalyst. This compound (III) methyl 2-(4-amino-3-flurophenyl)-2~-cyano propionate, is a readily recrystallizabl~, high melting white solid, easy to purify and stable. In contrast, the corresponding dimethyl malonate compound is an air-unstable oil, diffi~
cult to extract and purify, and subject to rapid darkening in air. Compound (III) as shown in the accompanying draw-ing, on the other hand, can be dried under vacuum at 50C, and stored for future use.

The next step o~ the pre~erred synthesis is the conversion of compound (III) to methyl 2-(2-fluoro-bipheny lyl)=2-cyano propionate, compound (IV). This is done by 2 ~L~ 9 2 ~ '~

making use of the Gomberg-Bachmann reaction, which involves diazotization of the amino group using an alkyl nitrite, followed by reaction with benzene~ A description of the Gomberg-Bachmann reaction can be found in "Advanced Organic Chemistry: Reactions Mechanisms and Structure," pages 550-551, 1968 (McGraw-Hill, Inc.), an article by March.

Compound (IV) resulting from the Gomberg-Bachmann reaction, can then be refluxed with aqueous acid or with aqueous alkali to convert it to the free acid, flurbi-profen, compound (V).

An alternative process according to the present invention first converts compound (II) to 2-(3-fluoro-4-nitrophenyl) propionic acid, compound (VI) by acid or alka-line hydrolysis. Then compound (VI) can be hydrogenated to form the 4-amino analog, compound (VII), using hydrogen over a platinum catalyst. Then compound (VII) can be subjected to the Gomberg-Bachmann reaction as described above to form flurbiprofen, compound (IV).

The invention is further described for illustra-tive purposes in the following specific examples.

~5 EXAMPLE 1 - METHYL 2-(3-FLUORO-4-NITROPHENYL)-2-CYANO
ACETATE

To a stirred mixture of 100 g (0.63 mole) of 2,4-difluoro nitroben~ene and 75 g (0.75 mole~ of methyl cyano acetate in 750 ml of dimethyl formamide at 0-10C and under an atmosphere of nitrogen, was added 65g (1~6 mole) of sodium hydroxide. After allowing to rise to room tempera~-ture, the reaction mixture was stirred overnight (about 16 hours). 1500 ml of water was added and the mixture acidified with dilute mineral acid to a pH of 2-3. The mixture was extracted with three lots of 500 ml ethyl 2 ~

acetate. The combined extracts were washed with several portions of dilute aqueous sodium sulphate and dried over sodium sulphate. Concentration under vacuo gave 150 g of oil.

EXAMPLE 2 - M~THYL 2-(3-FLUOKO-4 NITROPHENYL)-2 CYANO
PROPIONATE

A solution of 20g (84 mol) of methyl 2-(3-fluoro-4-nitrophenyl)-2-cyano acetate in ~0 ml of dry tetrahydro-furan was added drop-wise to a suspension of 5.0 g (0.125 mole) of 60~ oil-dispersed sodium hydroxide in 280 ml of tetrahydrofuran at 0C and under an atmosphere of nitrogen.
After evolution o~ hydrogen stopped, 12 g (0.095 mole) of dimethylsulfate was added. The mixture was heated to reflux for 8 hours and cooled in an ice-bath. Excess hydride was destroyed with some methanol. Aqueous 5%
sulfuric acid was added and the mixture extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated under vacuo to give crude methyl 2-(3-fluoro-4-nitrophenyl)-2-cyano propionate.

EXAMPLE 3 - METHYL 2-(3-FLUORO-4-NITROPHENYL)-2-CYANO
PROPIONATE - alternate method 2.8g (17.6 mmole) of 2,4-difluoronitrobenzene and 2.0g (17.7mmole) of methyl 2-cyanopropionate wreradded to 25 ml of dimethylformamid~ and cooled in an ice-bath. With vigourous stirring and under an atmosphere of nitrogen, 0.85g (21.3mmole) of sodium hydroxide was added. The mixture was stirred for 30 minutes in the ice-bath and then the ice-bath was removed. The reaction was then stirred overnight at room temperature. 20 ml of water was added and the mixture was extracted with 2x100 ml ethyl acetateO The organic layers were combined and washed with saturated aqueous sodium sulphate solution, dried over sodium sul-phate and concentrated under vacuo to give an oil.

. - ~ ' ~ ' EXAMPLE 4 - METHYL 2-(4-AMINO-3-FLUOROPHENYL)-2-CYANO
PROPIONATE __ _ A mixture of 24 g of crude methyl 2-(3-fluoro-4-nitrophenyl)-2-cyano propionate and 1.9 g of 5~ platinum-on-carbon catalyst in 200 ml of methanol was hydrogenated in a parr vessel at 20 - 25 psi of hydrogen pressure.
After the required amount of hydrogen was consumed, the reaction mixture filter and the filtrate concentrated under vacuo to give 21 g of an air-stable solid melting poink above 207C (decomposed).

EXAMPLE 5 - METHYL 2-(2-FLUORO-4-BIPHENYLYL)-2-CYANO
PROPIONATE
22g (99 mmol) of methyl 2-(4-amino-3-fluorophen-yl)-2-cyanopropionate was suspended in 600 ml of benzene and heated to 35 - 40C in an oil-bath. Then a solution of 35g (0.3mole) of isoamyl nitrite in 200 ml benzene was added dropwise over 1-2 hours. After the addition, the mixture was heated to 65 - 70C for 30 minutes and cooled to room temperature. Benzene was removed under vacuo to give a residue. Several portions of toluene were added and successively concentrated under vacuo. The resulting residue was triturated with a mixture of ethyl acetate and hexane to give a solid, m. pt. 186 - 189C.

EXAMPLE 6 - 2-(2-FLUORO-4-BIPHENYLYL)PROPIONIC ACID
(FLURBIPROF~N~ _ (a) A mixture containing 16 g of crude methyl 2-(2-fluoro-4-biphenylyl)-2-cyano propionate, 100 ml of 6N
aqueous hydrochloric acid and lOO ml of glacial acetic acid was refluxed under nitrogen for 30 hours. After cooling with an icebath (approximately 10C), the mixture was ~.

2~2~
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adjusted to pH 8.5 with 4N aqueous hydroxide and extracted with two lots of 100 ml methylene chloride. The aqueous layer was acidified with concentrated hydrochloric acid to pH 1-2 and cooled in a bath maintained at 5C with stir-ring. The precipitate was collected by filtration. The crude flurbiprofen was recrystalli~ed from aqueous acetic acid to give 11 g of solid.

(b) 10 g of methyl 2-(2-fluoro-4-biphenylyl) 2-cyano propionate was dissolved in 40 ml of ethanol. Then 30 g of 50% aqueous sodium hydroxide was added. The mixture was refluxed for 48 hours after diluting with 50 ml of water, the pH was adjusted to 8.5 and extracted with two lots of 100 ml methylene chloride. The a~ueous layer was acidified to pH below 2.0 and the precipitate was collected.
Recrystallization form aqueous acetic acid gave 6.6 g of flurbiprofen.

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Claims (11)

1. 2-(3-fluoro-4-nitrophenyl)-2-cyano-propionic acid lower alkyl esters.

2. Methyl-[2-(3-fluoro-4-nitrophenyl)-2-cyano]propionate.

3. Methyl-[2-(3-fluoro-4-aminophenyl)-2-cyano] propionate.

4. A process of preparing 2 (2-fluoro-3-nitrophenyl)-2-cyano-propionic acid lower alkyl esters, which comprises reacting a 2,4-difluoro nitrobenzene with a lower alkyl-(2-cyano) propionate.

5. The process of claim 4 wherein the lower alkyl -(2-cyano) propionate is methyl-(2-cyano) propionate.

6. A process of preparing 2-(3-fluoro-4-nitrophenyl)-2-cyano-propionic acid lower alkyl esters, which comprises reacting 2,4-difluoro nitrobenzene with 2-cyano acetic (lower alkyl) ester to form 2-(3-fluoro-4-nitrophenyl) 2-cyano acetic (lower alkyl) ester, and subsequently methylating the 2- position to form 2-(3-fluoro-4-nitrophenyl)-2-cyano propionic acid lower alkyl ester.

7. The process of claim 6 wherein said lower alkyl ester is a methyl ester.

8. A process of preparing 2-(2-fluoro-4-biphenylyl) propionic acid, which comprises:

reducing a 2-(3-fluoro-4-nitrophenyl)-2-cyano-propionic acid lower alkyl ester to the corresponding aniline derivative;

converting the aniline derivative so formed through the Gomberg-Bachmann reaction to form a 2-(2-fluoro-4-biphenylyl)-2-cyano propionic acid lower alkyl ester:

and hydrolysing the lower alkyl cyano-ester to form the free acid.

9. The process of claim 8 wherein the lower alkyl ester is the methyl ester.

10. A process of praparing 2-(2-fluoro-4-biphenylyl) propionic acid, which comprises hydrolysing a 2-(2-fluoro-3-nitrophenyl)-2-cyano-propionic acid lower alkyl ester to form 2-(2-fluoro-3-nitrophenyl) propionic acid;

reducing said nitrophenyl compound to the corre-sponding aniline derivative;

and converting the 3-amino phenol compound so formed through the Gomberg-Bachmann reaction to form 2-(2-fluoro-4-biphenylyl) propionic acid.

11. The process of claim 10 wherein the lower alkyl ester is a methyl ester.